5

Ethylene Chlorohydrin
1

Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory

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1This document was prepared by the AEGL Development Team composed of Robert Young (Oak Ridge National Laboratory), Heather Carlson-Lynch (SRC, Inc.), Julie Klotzbach (SRC, Inc.), Chemical Manager George Rusch (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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5 Ethylene Chlorohydrin1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory 1 This document was prepared by the AEGL Development Team composed of Robert Young (Oak Ridge National Laboratory), Heather Carlson-Lynch (SRC, Inc.), Julie Klot- zbach (SRC, Inc.), Chemical Manager George Rusch (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the doc- ument and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 262

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Ethylene Chlorohydrin 263 effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY Ethylene chlorohydrin is used in the manufacture of pesticides, plasticiz- ers, plant-protection agents, and dye intermediates. It is generally manufactured with a purity of greater than 99% with some being produced as an anhydrous grade. It is also used as a precursor in the production of ethylene oxide. An odor threshold of 0.4 ppm has been reported for ethylene chlorohydrin but data are not available from which to determine an acute level of odor awareness. Data on ethylene chlorohydrin were insufficient for deriving AEGL-1 val- ues. There were neither human nor animal data on AEGL-1 severity effects fol- lowing exposure to ethylene chlorohydrin vapor. Data on AEGL-2 severity effects in humans were not available. Because animal data involved either no lethality or 100% lethality, the concentration- response relationship for ethylene chlorohydrin vapor exposure is unknown. No data pertaining to AEGL-2 effects were available. Data in mice (Goldblatt 1944) showed there to be less than a four-fold difference between the concentration associated with a nonlethal response (280 ppm for 120 min) and the concentra- tion producing 100% lethality (1,090 ppm for 120 min), which suggests a steep exposure-response relationship. In accordance with NRC (2001) guidance, the AEGL-2 values were estimated as a three-fold reduction of the AEGL-3 values.

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264 Acute Exposure Guideline Levels The point-of-departure for deriving AEGL-3 values was 280 ppm for 120 min, which was the concentration that did not produce lethality in mice (Gold- blatt 1944). Values were scaled across time using the equation Cn × t = k. De- fault values for n of 3 for extrapolating to shorter durations and 1 when extrapo- lating to longer durations were used to derive values protective of human health (NRC 2001). Two uncertainty factors of 10 were applied; one to account for interspecies differences and one to account for intraspecies variability. Ethylene chlorohydrin does not appear to be a direct-contact irritant and death in animals does not appear to be a function of damaged epithelial tissue of the respiratory tract; however, the available data are not sufficient to conclusively describe the mechanism of toxicity. The AEGL values for ethylene chlorohydrin are presented in Table 5-1. 1. INTRODUCTION Ethylene chlorohydrin may be used in the manufacture of pesticides, plas- ticizers, plant-protection agents, and dye intermediates (HSDB 2005). It is gen- erally manufactured with a purity greater than 99% with some being produced as an anhydrous grade. It is a precursor in the production of ethylene oxide. Pro- duction volumes of 1.6-2.0 × 107 kg have been reported (HSDB 2005). The chemical and physical properties of ethylene chlorohydrin are pre- sented in Table 5-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Goldblatt and Chiesman (1944) described two cases originally reported by Koelsch (1927) involving acute exposure to ethylene chlorohydrin. In one case, a worker was exposed to ethylene chlorohydrin while cleaning a machine with a rag soaked in the chemical (dermal and inhalation exposure) for 2.5 h. Exposure concentrations were not measured and there was no report of the use of protec- tive equipment. He became nauseous and vomited and experienced a violent headache and giddiness. He died the next day, and autopsy showed inflammato- ry detachment of mucous membranes in the respiratory passages and pulmonitis of the right lung. The other case concerned one of four men involved in staining oil-cloth with dye mixed with ethylene chlorohydrin. Exposure concentrations were not measured and there was no report of the use of protective equipment. The man experienced nausea and narcosis and stopped working. The duration of exposure was not specified. He died in the evening after suffering from dyspnea, and autopsy showed cerebral and pulmonary edema, acute gastrointestinal ca- tarrh, renal degeneration, disease of the cardiac valves and aorta, and arterial calcification.

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Ethylene Chlorohydrin 265 TABLE 5-1 AEGL Values for Ethylene Chlorohydrin Classification 10 min 30 min 1h 4h 8h End Point (Reference) AEGL-1 NRa NRa NRa NRa NRa Insufficient data. (nondisabling) AEGL-2 2.1 ppm 1.5 ppm 1.2 ppm 0.47 ppm 0.23 ppm One-third of the AEGL-3 (disabling) (6.9 (4.9 (3.9 (1.5 (0.76 values (NRC 2001). mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 6.4 ppm 4.4 ppm 3.5 ppm 1.4 ppm 0.70 ppm Nonlethal exposure of (lethal) (21 (14 (12 (4.6 (2.3 mice at 280 ppm for 120 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) min (Goldblatt 1944). a Not recommended. Absence of an AEGL-1 value does not imply that exposures at con- centrations below the AEGL-2 value are without effect. TABLE 5-2 Chemical and Physical Data for Ethylene Chlorohydrin Parameter Value Reference Synonyms 2-chloroethanol; 2-chloro HSDB 2005 ethyl alcohol CAS registry no. 107-07-3 HSDB 2005 Chemical formula C2H5ClO HSDB 2005 Molecular weight 80.52 HSDB 2005 Physical state Liquid HSDB 2005 Melting point -67°C HSDB 2005 Boiling point 128-130°C HSDB 2005 Density/specific gravity 1.197 at 20°C HSDB 2005 Solubility in water 1 × 106 mg/L HSDB 2005 Relative vapor density 2.78 HSDB 2005 Vapor pressure 4.9 mm Hg at 20°C HSDB 2005 Saturated vapor concentration 645 ppm Calculated according to Perez and Solderholm (1991) Conversion factors in air 1 ppm = 3.29 mg/m3 NIOSH 2011 1 mg/m3 = 0.30 ppm Goldblatt and Chiesman (1944) also reported a fatality following exposure to ethylene chlorohydrin vapor. In one case, a worker became ill after exposure for about 1.5 h to vapors of ethylene chlorohydrin and ethylene dichloride while performing maintenance in an ethylene chlorohydrin tower. Exposure concentra- tions were not measured and there was no report of the use of protective equip- ment. He experienced repeated vomiting 1 h after the exposure, unsteadiness at 2 h, weak pulse and restlessness at 4 h, and low blood pressure and rales be- tween 4 and 11.5 h after exposure. He deteriorated rapidly and died 14 h after exposure. Autopsy showed congestion of the tracheal mucous membranes, marked and extensive collapse of the lungs, pulmonary edema, and cerebral congestion.

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266 Acute Exposure Guideline Levels Dierker and Brown (1944) reported a fatal case in which a man was ex- posed for 2 h to ethylene chlorohydrin and petroleum solvents during a cleaning operation. The worker wore rubber gloves to prevent dermal contact, but was exposed to solvent vapors by inhalation. He experienced nausea and vertigo and was later sent to a hospital for treatment. He was cyanotic with labored breath- ing and a slightly irregular pulse and died from respiratory failure that night. Autopsy showed congested lungs and kidneys, edema of the liver, and cloudy swelling of the renal tubules. Post-exposure estimates of the concentration of petroleum solvents and ethylene chlorohydrin were determined by resuming the cleaning operation and measuring the exposure concentration at the breathing level. The petroleum solvent concentration was 150-400 ppm and the average ethylene chlorohydrin concentration was estimated to be 305 ppm. Agricultural exposure to ethylene chlorohydrin during treatment of seed potatoes to enhance germination resulted in one death (Bush et al. 1949). The inhalation exposure concentration estimated by field and laboratory tests was 300-500 ppm. Dermal contact also occurred during the treatment process. The use of protective equipment was not reported. The worker experienced nausea, vomiting, dizziness, abdominal pain, weakness, and diminished vision after working several hours. He eventually returned to work, but collapsed several hours later and was transported to a hospital in a comatose condition where he died that night. Autopsy findings revealed fatty infiltration of the liver, edema of the brain and lungs, dilation of the heart chambers, degeneration of the myocar- dium, congestion of the spleen, cloudy swelling and hyperemia of the kidneys, petechial hemorrhages of the skin and conjunctiva, ascites, and hydrothorax. 2.2. Nonlethal Toxicity An odor threshold for ethylene chlorohydrin of 0.4 ppm has been reported (ACGIH 2001). Several nonfatal case reports of exposure to ethylene chlorohydrin vapor were summarized by Goldblatt and Chiesman (1944). These cases occurred dur- ing a time period where the average exposure concentration was 18 ppm. There was also likely concurrent exposure to ethylene dichloride. The exposure dura- tion was not specified and the use of protective equipment was not reported. A qualitative summary of signs and symptoms by organ system was provided: di- gestive system (nausea, epigastric pain, and vomiting); cardiovascular system (shock and depressed circulation); nervous system (headache, giddiness, incoor- dination, confusion, and mild narcotic effects); respiratory system (cough and rhonchi); and skin (erythema on arms and trunk in severe cases). In addition to the fatality described in Section 2.1, Bush et al. (1949) also reported nonlethal toxicity in five agricultural workers exposed intermittently to ethylene chlorohydrin at 300-500 ppm (estimated by field and laboratory tests). The exposure duration was not specified and the use of protective equipment was not reported. The workers experienced nausea, vomiting, irritation of the

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Ethylene Chlorohydrin 267 eyes, nose, and lungs, dizziness, diminished vision, and numbness of the hands and fingers. Four workers required hospitalization for treatment of symptoms. 2.3. Developmental and Reproductive Effects Data on the developmental and reproductive toxicity of ethylene chloro- hydrin in humans were not available. 2.4. Genotoxicity No information regarding the genotoxicity of ethylene chlorohydrin in humans was available. 2.5. Carcinogenicity Greenberg et al. (1990) reported an increased risk of mortality from pan- creatic cancer and leukemia in workers at a Union Carbide plant in which eth- ylene chlorohydrin was manufactured. In a 10-year follow-up of 278 male workers at the plant, Benson and Teta (1993) reported excess deaths from pan- creatic cancer (8 observed vs. 1.6 expected, SMR = 492 with 95% confidence interval of 158-1,140) and lymphopoietic and hematopoietic cancers (8 observed vs. 2.7 expected; SMR = 294 with 95% confidence interval of 127-580). Olsen et al. (1997) found no increased risk for these cancers in workers at Dow Chem- ical facilities. 2.6. Summary Human data with which to develop AEGL values are not available. Only qualitative information is available regarding the inhalation toxicity of ethylene chlorohydrin in humans. The available reports lack details about exposure and involved concurrent exposure to other chemicals. Case reports failed to provide definitive information regarding target organs or cause of death. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats Ambrose (1950) describe experiments in which groups of five adult male rats (strain not specified) were exposed using various exposure regimens and various dilutions of the test material. Various dilutions of ethylene chlorohydrin were placed in a bubbling tower immersed in a 40°C water bath. Air was passed through the tower and into the exposure chamber (neither air temperature nor air

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268 Acute Exposure Guideline Levels flow were specified, but air flow was noted as never exceeding 570 mL/min). No indication (other than the air flow value) was given that the possibility of aerosolization of the test material was considered. The inhalation exposure con- centrations associated with specific dilutions of ethylene chlorohydrin in water were not measured or estimated (whether vapor phase, aerosol, or mixed) in the study report. On the basis of the experimental results, the investigators noted that ethylene chlorohydrin was extremely toxic but deaths were delayed from 1- 24 h, depending on the concentration of the chemical in aqueous solution. The inhalation exposure concentrations associated with specific dilutions of ethylene chlorohydrin in water were not measured or estimated. Ambrose (1950) con- cluded that a 1-h exposure to ethylene chlorohydrin at 7.5 ppm and repeated exposure at 2 ppm was lethal to rats; however, the study did not describe the source of these air concentration values. In addition, the report did not specify the incidence of lethality at each concentration. Qualitatively, rats exhibited no signs of toxicity prior to ethylene chlorohydrin-induced lethality. Necropsy find- ings included cyanosis, dark blood, and “darker than normal” liver and kidneys. The reporting limitations associated with this study (lack of measured or esti- mated exposure concentrations, lack of lethality data) preclude the use of these data in deriving AEGL values. Goldblatt (1944) reported results of single exposure experiments in young adult rats (three animal per, strain and sex not specified) exposed to ethylene chlorohydrin vapor. The exposure apparatus consisted of a gas meter, flow me- ter, constant dropping apparatus, a suction system, and chambers for vaporiza- tion, mixing, and exposure. Air flow was maintained at 8-10 L/min and drop- ping of the test article was precisely controlled. Although no analytic data were provided, the investigator noted that the vapor concentration could be calculated within reasonable limits for any air flow or test article drop rate. It was stated that the ethylene chlorohydrin was pure but no data were provided. A 15-min exposure at 0.003 g/L (840 ppm, based on the conversion factor of 0.001 g/L = 280 ppm, v/v, reported by Goldblatt [1944]) and a 120-min exposure at 0.001 g/L (280 ppm) were not lethal whereas a 30-min exposure at 0.004 g/L (1,120 ppm) and 60-min exposure at 0.003 g/L (840 ppm) killed all three rats within 1 day (see Table 5-3). Narcosis was not produced and most exposure-related deaths occurred following the exposure rather than during the exposure. Histo- logic examinations revealed renal damage (medullary hemorrhage, hemolysis, and swollen and detached convoluted tubules) and areas of collapse in the lungs, but no pulmonary hemorrhage or edema. Goldblatt (1944) also described a repeated-exposure experiment in which three rats (strain and sex not specified) were exposed for 15 min/day to ethylene chlorohydrin at 0.002-0.005 g/L (about 560-1,400 ppm/day) for 11 days. One rat died on day 3, another on day 6, and a third on day 11. Observed signs included weight loss and lethargy. Urinalysis revealed no signs of renal toxicity although histologic examination of dead rats showed renal “congestion” and hemorrhage and hepatic congestion.

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Ethylene Chlorohydrin 269 A 4-h LC50 (lethal concentration, 50% lethality) value of 32 ppm for rats was reported in a review by Browning (1965). 3.1.2. Mice Dierker and Brown (1944) exposed six mice (sex not reported) to ethylene chlorohydrin at 365 ppm for 120 min. The atmosphere was maintained by evap- orating anhydrous ethylene chlorohydrin in an air stream through the exposure chamber. The animals became ill in less than 1 h. One mouse died 4 h after ex- posure from a respiratory-related cause. Examination showed pulmonary edema, capillary engorgement, and interstitial hemorrhages in the liver, kidney, and lungs. Goldblatt (1944) also reported lethality data for groups of three adult mice (strain and sex not specified) following single 15- to 120-min exposures to eth- ylene chlorohydrin (see Table 5-4). Experimental protocols were the same as those as described for rats in Section 3.1.1. TABLE 5-3 Lethality in Rats Following Single Exposure to Ethylene Chlorohydrin Concentrationa Duration (min) Effect 0.003 g/L (840 ppm) 15 Nonlethal 0.004 g/L (1,120 ppm) 30 3/3 dead next day 0.003 g/L (840 ppm) 60 Lethal next day 0.001 g/L (280 ppm) 120 Nonlethal a Three rats/group. Conversion of g/L to ppm based on 0.001 g/L = 280 ppm. Source: Adapted from Goldblatt 1944. TABLE 5-4 Lethality in Mice Following Single Exposure to Ethylene Chlorohydrin Concentrationa Duration (min) Effect 0.001 g/L (280 ppm) 120 Nonlethal 0.003 g/L (840 ppm) 60 3/3 dead next day 0.0032 g/L (896 ppm) 60 3/3 dead next day 0.0039 g/L (1,090 ppm) 15 2/3 dead after 2 days 0.0039 g/L (1,090 ppm) 120 3/3 dead in 140-170 min 0.0045 g/L (1,260 ppm) 30 3/3 dead next day 0.0052 g/L (1,460 ppm) 60 3/3 dead in 100 min to next day 0.007 g/L (1,960 ppm) 120 3/3 dead in 110-129 min a Three mice/group. Conversion of g/L to ppm based on 0.001 g/L = 280 ppm. Source: Adapted from Goldblatt 1944.

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270 Acute Exposure Guideline Levels In a toxicity study by Lawrence et al. (1971), duplicate groups of five male Swiss-Webster mice were exposed at various non-specified concentrations of ethylene chlorohydrin (99% pure) for 10-15 min. An LT50 (duration resulting in 50% lethality) of 13.3 min reported, but the data were insufficient for calcu- lating an LC50. Although the vapor concentration was not stated, the actual con- centration in the chamber was not constant and that equilibrium was likely oc- curring after 14 min. The data, which appeared to be from five exposure concentrations over the previously noted 10-15 min durations, were insufficient as a basis for any exposure-response estimate. 3.1.3. Guinea Pigs Lethality data for guinea pigs were reported by Goldblatt (1944) and are summarized in Table 5-5. Although the investigator suggested guinea pigs were less sensitive to the lethal effects of ethylene chlorohydrin, the data are for only one animal per exposure group. 3.1.4. Summary of Animal Lethality Data In studies of laboratory animals exposed to ethylene chlorohydrin, lethali- ty generally did not occur during exposure but was delayed from approximately 2 h to 1 day postexposure. Both interspecies and intraspecies variability in lethal response is evident, but the guinea pig data are based on a study that used only one animal per concentration. 3.2. Nonlethal Toxicity 3.2.1. Rats A 1-h exposure to ethylene chlorohydrin at 4 ppm was not lethal to rats (Ambrose 1950). Goldblatt (1944) reported that a single 15-min exposure of rats (sex and strain not specified) to ethylene chlorohydrin at 0.003 g/L (about 840 ppm) was not lethal. Exposed rats exhibited discomfort, closure of the eyes, and nasal irritation, but it was unclear whether the effects were observed in all of the rats or just those more severely affected. TABLE 5-5 Lethality in Guinea Pigs Following Single Exposure to Ethylene Chlorohydrin Concentrationa Exposure Duration (min) Effect 0.003 g/L (840 ppm) 30 Nonlethal 0.003 g/L (840 ppm) 120 Dead next day 0.0039 g/L (1,090 ppm) 108 Dead next day 0.005 g/L (1,400 ppm) 55 Nonlethal a One guinea pig/group. Conversion pf g/L to ppm based on 0.001 g/L = 280 ppm. Source: Adapted from Goldblatt 1944.

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Ethylene Chlorohydrin 271 3.2.2. Mice A 120-min exposure of mice (sex and strain not specified) to ethylene chlorohydrin at 0.001 g/L (about 280 ppm) was not lethal (Goldblatt, 1944). In the experiment by Dierker and Brown (1944), five of six mice survived a 120-min exposure to ethylene chlorohydrin at 365 ppm. The animals became ill less than an hour into the exposure, and displayed increased respiratory rates and minimal activity. Labored respiration was observed 4 h postexposure, and improvement was observed 6-h postexposure. The mice were reported to be normal 24 h after exposure and did not develop any untoward symptoms during a 1-week postexposure observation period. 3.2.3. Guinea Pigs A single 30-min exposure to ethylene chlorohydrin at 0.003 g/L (about 840 ppm) or a 55-min exposure at 0.005 g/L (about 1,400 ppm) was not lethal to guinea pigs (one animal/exposure) (Goldblatt 1944). 3.2.4. Cats Goldblatt (1944) reported that cats (number, sex, and breed were not spec- ified) exposed to ethylene chlorohydrin at concentrations of 10-15 mg/L (2,800- 4,200 ppm) for several hours showed no effects on blood pressure and no signs of respiratory disturbances regardless of whether the exposure was via a tracheal cannula or through the nasal passages. 3.2.5. Rabbits Goldblatt (1944) reported that rabbits (number, sex, and breed not speci- fied) exposed to ethylene chlorohydrin at concentrations of 10-15 mg/L (2,800- 4,200 ppm) for several hours showed no effects on blood pressure and no signs of respiratory disturbances regardless of whether the exposure was via a tracheal cannula or through the nasal passages. 3.2.6. Summary of Nonlethal Toxicity in Animals Available data do not precisely characterize the concentration-response re- lationship for nonlethal effects of exposure to ethylene chlorohydrin vapor. Most studies were lethality assays and, although identifying some exposures as nonle- thal, do not provide detailed information on the nature or severity of the effects (if any) that occurred. Generally, the exposure-response relationship is poorly defined.

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272 Acute Exposure Guideline Levels 3.3. Developmental and Reproductive Effects No information is available regarding the developmental and reproductive toxicity of ethylene chlorohydrin in animals following inhalation exposure. Re- sults of intravenous studies in CD-1 mice showed that ethylene chlorohydrin increased the incidence of malformed fetuses only at a dose that was associated with an increased maternal mortality (NTP 1983a). Studies in New Zealand white rabbits also intravenously exposed to ethylene chlorohydrin failed to demonstrate fetotoxic or teratogenic effects (NTP 1983b). 3.4. Genotoxicity NTP (1985) reported that ethylene chlorohydrin was mutagenic in Salmo- nella typhimurium strains TA100 and TA1535 with and without Aroclor- induced hamster or rat liver S9. Ethylene chlorohydrin was not mutagenic in strains TA1537 or TA98 and did not induce sex-linked recessive lethal muta- tions in Drosophila melanogaster. Overall, the compound is considered a weak base-pair substitution mutagen in bacteria. It is essentially negative in other test systems such as fungi, D. melanogaster, mammalian cell cultures, and rodents. 3.5. Carcinogenicity Information regarding the carcinogenicity of ethylene chlorohydrin fol- lowing inhalation exposure is not available. In dermal studies with rats and mice, NTP (1985) concluded that increases in incidences of lymphomas or leu- kemias, as well as increased incidences in alveolar/bronchiolar adenomas and carcinomas, were not treatment related. 3.6 Summary Lethality generally did not occur during inhalation exposure to ethylene chlorohydrin but rather was delayed from approximately 2 h to 1 day after expo- sure. Nonlethal effects were not well characterized and information was general- ly not available to describe the nature or severity of the effects. No information is available regarding the developmental and reproductive toxicity or carcino- genicity of ethylene chlorohydrin in animals following inhalation exposure. The chemical is considered a weak base-pair substitution mutagen in bacteria, but is essentially negative in other test systems such as fungi, D. melanogaster, mam- malian cell cultures, and rodents. 4. SPECIAL CONSIDERATIONS 4.1. Metabolism and Disposition There is no information on the metabolism and disposition of ethylene chlorohydrin following inhalation exposure. In Wistar rats, up to 80% of an oral-

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278 Acute Exposure Guideline Levels TABLE 5-9 Standards and Guidelines for Ethylene Chlorohydrin Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 NR NR NR NR NR AEGL-2 2.1 ppm 1.5 ppm 1.2 ppm 0.47 ppm 0.23 ppm (6.9 mg/m3 (4.9 mg/m3) (3.9 mg/m3) (1.5 mg/m3) (0.76 mg/m3) AEGL-3 6.4 ppm 4.4 ppm 3.5 ppm 1.4 ppm 0.70 ppm (21 mg/m3) (14 mg/m3) (12 mg/m3) (4.6 mg/m3) (2.3 mg/m3) IDLH (NIOSH)a – 7 ppm – – – (23 mg/m3) PEL-TWA – – – – 5 ppm (OSHA)b (16 mg/m3) TLV-C (ACGIH)c 1 ppm 1 ppm 1 ppm 1 ppm 1 ppm (3.3 mg/m3) (3.3 mg/m3) (3.3 mg/m3) (3.3 mg/m3) (3.3 mg/m3) REL-C (NIOSH)d 1 ppm 1 ppm 1 ppm 1 ppm 1 ppm (3.3 mg/m3) (3.3 mg/m3) (3.3 mg/m3) (3.3 mg/m3) (3.3 mg/m3) MAK (Germany)e – – – – 1 ppm (3.3 mg/m3) MAC – – – – 1.0 ppm (the Netherlands)f (3 mg/m3) a IDLH (immediately dangerous to life or health, National Institute for Occupational Safe- ty and Health) (NIOSH 1994) represents the maximum concentration from which one could escape within 30 min without any escape-impairing symptoms, or any irreversible health effects. b PEL-TWA (permissible exposure limit – time-weighted average, Occupational Health and Safety Administration) (29 CFR 1910.1000 [2013]) is defined as an employee’s ex- posure to any substance that shall not exceed the 8-h TWA given for that substance in any 8-h work shift of a 40-h work week. The PEL for ethylene chlorohydrin includes a skin notation. c TLV-C (threshold limit value – ceiling, American Conference of Governmental Industri- al Hygienists) (ACGIH 2001, 2012) is the concentration that should not be exceeded at any time. The TLV-ceiling for ethylene chlorohydrin includes a skin notation. d REL-C (recommended exposure limit – ceiling, National Institute for Occupational Safety and Health) (NIOSH 2011) is defined as the value that should not be exceeded at any time. The REL ceiling for ethylene chlorohydrin includes a skin notation. e MAK (maximale arbeitsplatzkonzentration [maximum workplace concentration], Deutsche Forschungsgemeinschaft [German Research Association], Germany) (DFG 2002) is defined analogous to the OSHA PEL-TWA. The MAK for ethylene chlorohy- drin includes a skin notation. f MAC (maximaal aanvaaarde concentratie [maximal accepted concentration]), Dutch Expert Committee for Occupational Standards, The Hague, The Netherlands) (MSZW 2004) is defined analogous to the OSHA PEL-TWA. The MAC for ethylene chlorohydrin includes a skin notation.

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Ethylene Chlorohydrin 279 8.3. Data Adequacy and Research Needs Data reported for human exposure to ethylene chlorohydrin demonstrate systemic effects of ethylene chlorohydrin and add support to the toxicologic end points of the animal data. Quantitative animal data are available from a few in- halation studies of rats, mice, guinea pigs, cats, and rabbits. The data demon- strate toxicity outcomes in animals that are similar to those observed in humans. Although the animal data provide information on lethal and nonlethal exposures, data used to derive AEGL-3 values are from a single dose-ranging study that used a small number of animals. Additional data providing information at expo- sures that are irritating or nonincapacitating would be useful for deriving AEGL- 1 values and refining AEGL-2 values. Additional data are needed with respect to the exposure-response relationship and mode of action of ethylene chlorohydrin vapor exposure. 9. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2001. Ethylene chlorohydrin (CAS Reg. No. 107-07-3). Documentation of the Threshold Limit Values and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hygienists). 2012. Ethylene chlorohydrin (CAS Reg. No. 107-07-3). 2012 TLVs and BEIs Based on the Doc- umentation of the Threshold Limit Values for Chemical Substance and Physical Agents. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Ambrose, A.M. 1950. Toxicological studies of compounds investigated for use as inhibi- tors of biological processes. II. Toxicity of ethylene chlorohydrin. AMA Arch. Ind. Hyg. Occup. Med. 2(5):591-597. Benson, L.O., and M.J. Teta. 1993. Mortality due to pancreatic and lymphopoietic can- cers in chlorohydrin production workers. Br. J. Ind. Med. 50(8):710-716. Browning, E. 1965. Ethylene chlorohydrin. Pp. 397-401 in Toxicity and Metabolism of Industrial Solvents. New York: Elsevier. Bush, A.F., H.K. Abrams, and H.V. Brown. 1949. Fatality and illness caused by ethylene chlorohydrin in an agricultural occupation. J. Ind. Hyg. Toxicol. 31(6):352-358. DFG (Deutsche Forschungsgemeinschaft). 2002. 2-Chlorethanol. The MAK Collection for Occupational Health and Safety. Wiley-Online Library [online]. Available: http://onlinelibrary.wiley.com/doi/10.1002/3527600418.mb10707d0034/full [ac- cessed Apr. 8, 2014]. Dierker, H., and P.G. Brown. 1944. Study of a fatal case of ethylene chlorohydrin poison- ing. J. Ind. Hyg. Toxicol. 26: 277-279. Goldblatt, M.W. 1944. Toxic effects of ethylene chlorohydrin. Part II. Experimental. Br. J. Ind. Med. 1(4):213-223. Goldblatt, M.W., and W.E. Chiesman. 1944. Toxic effects of ethylene chlorohydrin. Part I. Clinical. Br. J. Ind. Med. 1(4):207-213. Greenberg, H.L., M.G. Ott, and R.E. Shore. 1990. Men assigned to ethylene oxide pro- duction or other ethylene oxide related chemical manufacturing: A mortality study. Br. J. Ind. Med. 47(4):21-30.

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280 Acute Exposure Guideline Levels Grunow, W., and H.J. Altmann. 1982. Toxicokinetics of chloroethanol in the rat after single oral administration. Arch. Toxicol. 49(3-4): 275-284. Haber, F. 1924. The history of the gas war. Pp. 76-92 in Five Lectures from the Years 1920-1923, F. Haber, ed. [in German]. Berlin: Springer. HSDB (Hazardous Substances Data Bank). 2005. 2-Chloroethanol (CAS Reg. No. 107- 07-3). TOXNET, Specialized Information Services, U.S. National Library of Med- icine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/html gen?HSDB [accessed Apr. 8, 2014]. Johnson, M.K. 1965. The influence of some aliphatic compounds on rat liver glutathione levels. Biochem. Pharmacol. 14(9):1383-1385. Johnson, M.K. 1967. Metabolism of chloroethanol in the rat. Biochem. Pharmacol. 16(1):185-199. Koelsch, F. 1927. The toxicity of the ethylene chlorohydrins. Zentralbl. Gewerbehyg. 4:312-316 (as cited in Goldblatt and Chiesman 1944). Lawrence, W.H., J.E. Turner, and J. Autian. 1971. Toxicity of ethylene chlorohydrin. I. Acute toxicity studies. J. Pharm. Sci. 60(4):568-571. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: 2-Chloorethanol. Den Haag: SDU Uitgevers [online]. Available: http://www.lasrook.net/lasrookNL/maclijst2004.htm [accessed Apr. 8, 2014]. NIOSH (National Institute for Occupational Safety and Health). 1994. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLHs): Ethylene chlo- rohydrin. National Institute for Occupational Safety and Health [online]. Availa- ble: http://www.cdc.gov/niosh/idlh/107073.html [accessed July 2013]. NIOSH (National Institute of Occupational Safety and Health). 2011. Pocket Guide to Chemical Hazards: Ethylene chlorohydrin. National Institute for Occupational Safety and Health [online]. Available: http://www.cdc.gov/niosh/npg/npgd0268.html [ac- cessed July 2013]. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NTP (National Toxicology Program). 1983a. Teratologic Evaluation of Ethylene Chloro- hydrin (CAS Reg. No. 107-07-3) in CD-1 Mice. NTP studies TER84070A, TER84070B, TER84070C, and TER84070D. U.S. Department of Health and Hu- man Services, Public Health Service, National Institute of Health, National Toxi- cology Program, Research Triangle Park, NC. NTP (National Toxicology Program). 1983b. Teratologic Evaluation of Ethylene Chloro- hydrin (CAS Reg. No. 107-07-3) in New Zealand White Rabbits. NTP study TER84071. U.S. Department of Health and Human Services, Public Health Ser- vice, National Institute of Health, National Toxicology Program, Research Trian- gle Park, NC. NTP (National Toxicology Program). 1985. Toxicology and Carcinogenesis Studies of 2-Chloroethanol (Ethylene Chlorohydrin) (CAS Reg. No. 107-07-3) in F344/N Rats and Swiss CD-1 Mice (Dermal Studies). NTP TR 275. NIH 86-2531. U.S. Depart- ment of Health and Human Services, Public Health Service, National Institute of Health, National Toxicology Program, Research Triangle Park, NC. November 1985 [online]. Available: http://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr275.pdf [accessed Apr. 8, 2014].

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Ethylene Chlorohydrin 281 Olsen, G.W., S.E. Lacy, K.M. Bodner, M. Chau, T.G. Arceneaux, J.B. Cartmill, J.M. Ramlow, and J.M. Boswell. 1997. Mortality from pancreatic and lymphoietic can- cer among workers in ethylene and propylene chlorohydrin production. Occup. Environ. Med. 54:592-598. Patty, F.A., ed. 1963. β-Chloroethyl alcohol. Pp. 1492-1496 in Industrial Hygiene and Toxicology, Vol. Toxicology, 2nd Rev. Ed. New York: John Wiley and Sons. Perez, C., and S.C. Soderholm. 1991. Some chemicals requiring special consideration when deciding whether to sample the particle, vapor, or both phases of an atmos- phere. Appl. Occup. Environ. Hyg. 6(10):859-864. Rinehart, W. E., and T. Hatch. 1964. Concentration-time product (CT) as an expression of dose in sublethal exposures to phosgene. Ind. Hyg. J. 25(6):545-553. ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(3):301-309.

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282 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR ETHYLENE CHLOROHYDRIN Derivation of AEGL-1 Values Because of insufficient data regarding AEGL-1 severity effects and the overall exposure-response relationship for ethylene chlorohydrin vapor exposure, AEGL-1 values are not recommended. Absence of AEGL-1 values does not imply that expo- sures below the AEGL-2 values are without effect. Derivation of AEGL-2 Values Because of insufficient data on AEGL-2 severity effects, the AEGL-2 values were estimated as one-third of the AEGL-3 values as per guidance in NRC (2001). The lethality data in rats, mice, and guinea pigs indicate a steep exposure-response relationship. 10-min AEGL-2: 6.4 ppm ÷ 3 = 2.1 ppm 30-min AEGL-2: 4.4 ppm ÷ 3 = 1.5 ppm 1-h AEGL-2: 3.5 ppm ÷ 3 = 1.2 ppm 4-h AEGL-2: 1.4 ppm ÷ 3 = 0.47 ppm 8-h AEGL-2: 0.70 ppm ÷ 3 = 0.23 ppm Derivation of AEGL-3 Values Key study: Goldblatt, M.W. 1944. Toxic effects of ethylene chlorohydrin. Part II. Experimental. Br. J. Ind. Med. 1(4):213-223. Critical effect: A 120-min nonlethal exposure at 280 ppm in mice was used as an estimated lethality threshold. A 120-min exposure at 1,090 ppm resulted in 100% lethality. Time scaling: Cn × t = k, where n = 1 or 3 (NRC 2001) Uncertainty factors: 10 for interspecies differences 10 for intraspecies variability; ethylene chlorohydrin does not appear to be a direct-contact irritant and death in animals does not appear to be a function of damaged respiratory tract epithelial tissue. In the absence of data

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Ethylene Chlorohydrin 283 regarding the mode of action of ethylene chlorohydrin toxicity and because of the small numbers of animals used in the reported studies, an intraspecies uncertainty of 10 is retained. Sensitive populations could not be identified. Modifying factor: None applied Calculation: (280 ppm)1 × 120 min = 560 ppm-h (280 ppm)3 × 120 min = 43,904,000 ppm-h 10-min AEGL-3: C3 × 10 min = 43,904,000 ppm-h C = 637 ppm C = 637 ppm ÷ 100 = 6.4 ppm 30-min AEGL-3: C3 × 30 min = 43,904,000 ppm-h C = 444 ppm C = 444 ppm ÷ 100 = 4.4 ppm 1-h AEGL-3: C3 × 60 min = 43,904,000 ppm-h C = 353 ppm C = 353 ppm ÷ 100 = 3.5 ppm 4-h AEGL-3: C × 240 min = 560 ppm-h C = 140 ppm C = 140 ppm ÷ 100 = 1.4 ppm 8-h AEGL-3: C × 480 min = 560 ppm-h C = 70.0 ppm C = 70.0 ppm ÷ 100 = 0.70 ppm

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284 Acute Exposure Guideline Levels APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR ETHYLENE CHLOROHYDRIN Derivation Summary AEGL-1 VALUES Because of insufficient data regarding AEGL-1 severity effects and the overall exposure-response relationship for ethylene chlorohydrin vapor expo- sure, AEGL-1 values are not recommended. Absence of AEGL-1 values does not imply that exposures below the AEGL-2 values are without effect. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 2.1 ppm 1.5 ppm 1.2 ppm 0.47 ppm 0.23 ppm (6.9 mg/m3) (4.9 mg/m3) (3.9 mg/m3) (1.5 mg/m3) (0.76 mg/m3) Data adequacy: Data on ethylene chlorohydrin were insufficient for deriving AEGL-2 values. In accordance with NRC (2001) guidance, AEGL-2 values were estimated by dividing the AEGL-3 values by 3. Animal lethality data indicate a steep exposure- response relationship for ethylene chlorohydrin. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 6.4 ppm 4.4 ppm 3.5 ppm 1.4 ppm 0.70 ppm (21 mg/m3) (14 mg/m3) (12 mg/m3) (4.6 mg/m3) (2.3 mg/m3) Reference: Goldblatt, M.W. 1944. Toxic effects of ethylene chlorohydrin. Part II. Experimental. Br. J. Ind. Med. 1(4):213-223. Test Species/Strain/Sex/Number: Mouse; strain and gender not specified; 3/group Exposure route/Concentrations/Durations: Inhalation Concentration (ppm) Duration (min) Effect 280a 120 No lethality 1,090 120 3/3 dead at 140-170 min 1,960 120 3/3 dead at 110-129 min a Concentration used as the point-of-departure for AEGL-3 derivation. Effects: Signs of discomfort and irritation, and incoordination at higher concentrations (group-specific observations were not provided) and death. End point/Concentration/Rationale: Lowest concentration with no mortality (280 ppm for 120 min) Uncertainty factors/Rationale: Interspecies: 10, absence of information available to describe species differences in toxicity. Intraspecies: 10, ethylene chlorohydrin does not appear to be a direct-contact irritant and

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Ethylene Chlorohydrin 285 death in animals does not appear to be a function of damaged respiratory tract epithelial tissue. In the absence of data regarding the mode of action of ethylene chlorohydrin toxicity and because of the small numbers of animals used in the studies, a factor of 10 is retained. Modifying factor: None applied Animal-to-human dosimetric adjustment: Not applicable Time scaling: Cn × t = k, where n = 1 for extrapolation to longer durations or n = 3 for extrapolation to shorter durations (NRC 2001) Data adequacy: Marginal; the exposure-response relationship is not fully defined by the available data; animal data are based on exposures with only three animals per group.

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286 Ac cute Exposure Guideline Levels AP PPENDIX C CATEGORY PLOT FOR ETHYLENE CHLOROH Y R E HYDRIN FIGUR C-1 Category plot of toxicity data and AEGL values for ethy RE y y L ylene chlorohydr rin.

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TABLE C-1 Data Used in Category Plot of Ethylene Chlorohydrin Source Species Sex No. Exposures ppm Minutes Category Comments AEGL-1 NR 10 AEGL AEGL-1 NR 30 AEGL AEGL-1 NR 60 AEGL AEGL-1 NR 240 AEGL AEGL-1 NR 480 AEGL AEGL-2 2.1 10 AEGL AEGL-2 1.5 30 AEGL AEGL-2 1.2 60 AEGL AEGL-2 0.47 240 AEGL AEGL-2 0.23 480 AEGL AEGL-3 6.4 10 AEGL AEGL-3 4.4 30 AEGL AEGL-3 3.5 60 AEGL AEGL-3 1.4 240 AEGL AEGL-3 0.7 480 AEGL Goldblatt 1944 Rat 1 840 15 1 Nonlethal; no details but minor effects possible. Rat 1 1,120 30 3 100% lethality. Rat 1 678 60 3 Lethal Rat 1 226 120 1 Nonlethal; no details but minor effects possible. 287 (Continued)

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288 TABLE C-1 Continued Source Species Sex No. Exposures ppm Minutes Category Comments Mouse 1 280 120 1 Nonlethal; no details but minor effects possible. Mouse 1 840 60 3 100% lethality Mouse 1 896 60 3 100% lethality Mouse 1 1,090 15 SL Lethal Mouse 1 1,090 120 3 Lethal Mouse 1 1,260 30 3 Lethal Mouse 1 1,460 60 3 Lethal Mouse 1 1,960 120 3 Lethal Guinea pig 1 840 30 1 Nonlethal; no details but minor effects possible. Guinea pig 1 840 120 3 Lethal Guinea pig 1 1,090 108 3 Lethal Guinea pig 1 1,460 55 1 Nonlethal; no details but minor effects possible. Patty 1963 Rat 1 32 240 3 LC50 no details. Dierker and Brown 1944 Human 1 300 120 3 Human lethality (estimated exposure concentration). For category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal